Maurya Ranjani, Soni Awakash, Anand Devireddy, Ravi Makthala, Raju Kanumuri S R, Taneja Isha, Naikade Niraj K, Puri S K, Kanojiya Sanjeev, Yadav Prem P
Division of Medicinal & Process Chemistry, Division of Parasitology, Division of Pharmacokinetics and Metabolism, and Sophisticated Analytical Instrument Facility, Central Drug Research Institute , Lucknow-226001, India.
ACS Med Chem Lett. 2012 Dec 11;4(2):165-9. doi: 10.1021/ml300188t. eCollection 2013 Feb 14.
Novel 3,3-spiroanellated 5-aryl, 6-arylvinyl-substituted 1,2,4-trioxanes 19-34 have been synthesized and appraised for their antimalarial activity against multidrug-resistant Plasmodium yoelii nigeriensis in Swiss mice by oral route at doses ranging from 96 mg/kg × 4 days to 24 mg/kg × 4 days. The most active compound of the series (compound 25) provided 100% protection at 24 mg/kg × 4 days, and other 1,2,4-trioxanes 22, 26, 27, and 30 also showed promising activity. In this model, β-arteether provided 100 and 20% protection at 48 mg/kg × 4 days and 24 mg/kg × 4 days, respectively, by oral route. Compound 25 displayed a similar in vitro pharmacokinetic profile to that of reference drug β-arteether. The activity results demonstrated the importance of an aryl moiety at the C-5 position on the 1,2,4-trioxane pharmacophore.
新型3,3-螺环缩合的5-芳基、6-芳基乙烯基取代的1,2,4-三氧杂环己烷19 - 34已被合成，并通过口服途径在瑞士小鼠中对多重耐药的约氏疟原虫尼日尔株进行抗疟活性评估，剂量范围为96 mg/kg×4天至24 mg/kg×4天。该系列中活性最高的化合物（化合物25）在24 mg/kg×4天时提供了100%的保护，其他1,2,4-三氧杂环己烷22、26、27和30也显示出有前景的活性。在该模型中，蒿甲醚通过口服途径在48 mg/kg×4天和24 mg/kg×4天时分别提供了100%和20%的保护。化合物25显示出与参考药物蒿甲醚相似的体外药代动力学特征。活性结果证明了1,2,4-三氧杂环己烷药效基团C-5位上芳基部分的重要性。
